1. Field of the Invention
The present invention relates to benzene compounds, and more particularly, to novel benzene compounds having inhibition activity on acetyl CoA carboxylase (“ACC” hereinafter).
2. Discussion of the Background
It has become clear in recent years that obesity is an important risk factor for arteriosclerosis, particularly coronary artery disease. That is, it has been reported that in obese individuals, various factors such as fatty acids and TNF-α are released from accumulated visceral fat tissue, inducing insulin resistance in skeletal muscle, the liver, and fat tissue, accelerating the synthesis of neutral fat in the liver, and inducing hyperlipemia. Further, the heightened level of insulin in the blood resulting from insulin resistance not only causes impaired glucose tolerance, especially diabetes, but also stimulates renal reabsorption of Na ions and activates the sympathetic nerves, thereby increasing peripheral vascular resistance and finally resulting in hypertensive symptoms. The hyperlipemia, diabetes, and hypertension resulting from obesity cause vascular blockage such as cerebrovascular blockage and coronary artery disease as a result of arteriosclerosis, and are thought to greatly affect an individual's life prognosis.
The foundations for treating obesity are kinetotherapy and dietetic therapy. However, due to conflict with basic human desires, the necessity of striking a balance with time spent working, increased stress, and a variety of other factors, numerous difficulties present themselves when trying to achieve set objectives. Extremely obese persons sometimes undergo surgical treatment such as stomach-reducing operations and stomach bypassing surgery. However, when an obese person undergoes an abdominal operation, complications such as infection and steatolysis often result, a great amount of time is lost, and pain is experienced. Accordingly, it is considered necessary to combine the use of drugs capable of safely and easily complementing exercise and diet therapies. Examples of pharmaceuticals currently employed as anti-obesity agents are central nervous system appetite depressants such as mazindol and sibutramine and pancreatic lipase inhibitors such as orlistat. Drugs acting on the central nervous system sometimes produce severe side effects such as thirst, constipation, stomach discomfort, and on occasion, auditory and visual hallucination. Orlistat has been found to have digestive tract side effects such as diarrhea, incontinence, and flatulence. In general, these anti-obesity drugs are only slightly effective at dosages that do not produce side effects, the safety of these drugs with long-term use has yet to be established, and they have seldom been found to have an advantageous effect with regard to insulin resistance, which is closely linked to obesity.
Treatments employing biguanide agents and agonists of peroxisome proliferator-activated receptor (“PPAR” hereinafter) γ are widely employed for insulin resistance. Biguanide agents are reported to afford improvement with regard to insulin resistance and have blood-glucose-lowering and hyperlipemia-improving actions, primarily in patients with non-insulin dependent diabetes. However, single-drug treatment is not adequately effective, and it has become clear that these drugs present life-threatening side effects such as lactic acid acidosis in addition to digestive organ symptoms such as upper abdominal discomfort, nausea, and diarrhea. Similar to biguanide agents, PPAR-γ agonists afford improvement in insulin resistance, hyperglycemia, and hyperlipemia in non-insulin dependent diabetes patients, but cannot yet be considered satisfactory with regard to side effects (obesity, severe hepatitis).
ACC, an enzyme catalyzing the synthesis of malonyl CoA from acetyl CoA, is a rate-determining enzyme in the synthesis of long-chain fatty acids. The malonyl CoA that is synthesized from acetyl CoA by ACC is known to negatively control carnitine acyltransferase involved in the consumption of free long-chain fatty acids as an energy source. ACC activation is also thought to contribute to fatty acid synthesis in visceral fat tissue. Accordingly, drugs that inhibit ACC may not only block the synthesis of new long-chain fatty acids and neutral fat in the body, but may also serve as treatment agents and preventive agents for obesity symptoms and various illnesses resulting from obesity-induced hyperlipemia and insulin resistance by reducing existing fat tissue. Examples of compounds known to block ACC in mammals are acylsulfonamide derivatives, 5-(tetradecyloxy)-2-furoic acid, and biotin derivatives. It has become clear that acylsulfonamide derivatives promote the glucose uptake by skeletal muscle cells in vitro and have an effect on reducing blood glucose in diabetic model animals. Their usefulness as pharmaceuticals in humans has also been prospective (see, JP-A-11-171847, JP-A-11-171848, JP-A-11-171856, WO02/02517, WO02/02101, WO03/59886, WO03/59871, J. Biol. Chem., vol. 226, pp. 497-509 (1957), J. Biol. Chem., vol. 77, pp 16347-16350 (2002)).